Roles of membrane type 1 matrix metalloproteinase and tissue inhibitor of metalloproteinases 2 in invasion and dissemination of human malignant glioma

J Neurosurg. 2001 Mar;94(3):464-73. doi: 10.3171/jns.2001.94.3.0464.


Object: Acquisition of invasive and metastatic potentials through proteinase expression is an essential event in tumor progression. Among proteinases, matrix metalloproteinases (MMPs) are thought to play a key role in tumor progression through the degradation of the extracellular matrix. In the present study, the authors examined the role of MMP-2 (gelatinase A) and membrane type 1 MMP (MT1-MMP), an activator of the zymogen of MMP-2, proMMP-2, together with tissue inhibitors of metalloproteinases (TIMP-1 and TIMP-2) in the invasion of astrocytic tumors in humans.

Methods: Analyses performed using sandwich enzyme immunoassays demonstrated that the production levels of pro-MMP-2 and TIMP-1, but not TIMP-2, are significantly higher in glioblastomas multiforme than in other grades of astrocytic tumors. Quantitative reverse transcription-polymerase chain reaction indicated that MT1-MMP is expressed predominantly in glioblastoma tissues, and its expression levels are significantly enhanced as tumor grade increases. In addition, the expression levels and proMMP-2 activation ratio were remarkably higher in glioblastomas associated with cerebrospinal fluid (CSF) dissemination than in those not associated with CSF dissemination. In contrast, an examination of TIMP-2 levels showed a reverse correlation. Like MT1-MMP, TIMP-1 and TIMP-2 were immunolocalized to neoplastic cells in glioblastoma samples. To study the roles of these molecules in the invasion of astrocytic tumors more fully, stable transfectants expressing the MT1-MMP gene were developed in a U251 human glioblastoma cell line. The MT1-MMP transfectants displayed prominent activation of proMMP-2 and invasive growth in three-dimensional collagen gel; however, mock transfectants and parental cells displayed noninvasive growth without the activation. The invasion and gelatinolytic activity of the transfectants were completely inhibited by addition of recombinant TIMP-2, but not recombinant TIMP-1.

Conclusions: These results indicate that MT1-MMP may contribute to tumor invasion and CSF dissemination of glioblastoma cells on the basis of an imbalance of TIMP-2.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Astrocytoma / enzymology*
  • Astrocytoma / pathology*
  • Brain Neoplasms / enzymology*
  • Brain Neoplasms / pathology*
  • Cell Division
  • Collagen
  • Enzyme Precursors / analysis
  • Enzyme Precursors / metabolism
  • Gelatin / metabolism
  • Gelatinases / analysis
  • Gelatinases / metabolism
  • Gels
  • Gene Expression Regulation, Enzymologic
  • Humans
  • Immunoenzyme Techniques
  • Immunohistochemistry
  • Matrix Metalloproteinase 1 / analysis
  • Matrix Metalloproteinase 1 / genetics
  • Matrix Metalloproteinase 1 / metabolism*
  • Metalloendopeptidases / analysis
  • Metalloendopeptidases / metabolism
  • Neoplasm Invasiveness / pathology
  • RNA, Messenger / analysis
  • Tissue Inhibitor of Metalloproteinase-1 / analysis
  • Tissue Inhibitor of Metalloproteinase-1 / metabolism
  • Tissue Inhibitor of Metalloproteinase-2 / analysis
  • Tissue Inhibitor of Metalloproteinase-2 / metabolism*
  • Transfection
  • Tumor Cells, Cultured


  • Enzyme Precursors
  • Gels
  • RNA, Messenger
  • Tissue Inhibitor of Metalloproteinase-1
  • Tissue Inhibitor of Metalloproteinase-2
  • Gelatin
  • Collagen
  • Gelatinases
  • Metalloendopeptidases
  • progelatinase
  • Matrix Metalloproteinase 1